Overweight and obesity are among the leading causes of preventable deaths in the US, primarily through their effects on Type II diabetes mellitus and other cardiovascular disease risk factors. Individuals with serious mental illness represent a large underserved population at greatly increased risk of obesity, diabetes, metabolic syndrome, and subsequent early mortality. These risks are amplified by the antipsychotic agents that are often prescribed to treat these mental conditions. Although strong evidence indicates that lifestyle interventions are effective at reducing weight and other diabetes risk factors in general populations, and pilot and feasibility studies suggest that such interventions will be effective with individuals who have mental illnesses, no large-scale translational trials have examined such interventions in this population. In responding to PAR-06-532, Translational Research for the Prevention and Control of Diabetes, this application seeks to fill that evidence gap. We propose a randomized controlled trial to examine the effectiveness, in a mentally ill population, of a lifestyle intervention previously shown to be effective for reducing weight and diabetes risk factors. We target a group of individuals taking antipsychotic agents (n = 280) who receive treatment in one of two clinical settings - a publicly funded behavioral health care clinic and a non-profit private health plan. Counselors from each clinical setting will be trained in the intervention and paired with study staff to deliver it, increasing generalizability, and improving the probability of future adoption. The intervention promotes moderate calorie reduction, dietary changes, and increased energy expenditure, and is based on current clinical practice guidelines for treating obesity and cardiovascular disease. Specific aims test the hypotheses that the intervention is more effective than usual care in: 1) reducing weight and BMI; 2) reducing fasting insulin levels and increasing insulin sensitivity; and 3) reducing total cholesterol and LDL cholesterol, with outcomes assessed at 6, 12, and 24 months. A fourth aim explores effects of motivation, social support, and outcomes expectancies on primary outcomes, and moderators of intervention effectiveness (ethnicity, gender, mental illness diagnostic group, medication type, metabolic syndrome). Implementation and process evaluations will assess the fidelity of intervention delivery, evaluate its acceptability; identify components participants find most and least helpful; identify barriers to, and facilitators of, lifestyle changes; and evaluate the effects of the intervention on body image, psychiatric symptoms, adherence to antipsychotic medications, quality of life, health-related self-efficacy, health, functional status, and social support. Cost-effectiveness analyses will evaluate incremental costs of producing change in each primary outcome (weight, BMI, fasting insulin levels, insulin sensitivity, and cholesterol). PUBLIC HEALTH RELEVANCE: This study will examine whether a lifestyle change program to reduce weight and diabetes risk factors will be effective among people with serious mental illnesses. If the results are positive, it could help people with mental illness improve their health and reduce their diabetes risk.